Genome‐wide identification of modifiers of age‐at‐onset for Alzheimer’s disease in African American populations

Abstract

AbstractBackgroundSeveral studies have attempted to identify genes for age‐at‐onset (AAO) of Alzheimer’s disease (AD) through genome‐wide linkage and genome‐wide association studies (GWAS). While these efforts have thus far focused predominantly on non‐Hispanic white (NHW) populations, we present here the first GWAS to identify genetic contributors to AAO in African Americans (AA) using AA genotype and phenotype data from the Alzheimer’s Disease Genetics Consortium (ADGC).MethodWe combined data from 13 AA prospective and case‐control ADGC datasets, excluding family‐based datasets. Genotype data underwent standard quality control and were imputed to the TOPMed R5 reference panel using the Michigan Imputation Server. Data were merged across cohorts using QCTOOL and GTOOL, filtering out variants with MAF≤0.005). We performed two analyses: case‐only linear mixed‐model regression with AAO as outcome (LMM); and survival analysis using Cox proportional‐hazards frailty modeling (COXPHF) with time‐to‐AD‐onset (AAO in cases and censoring of controls at age‐at‐last‐exam). Both models were adjusted for sex, principal components capturing population substructure, and APOE‐ε4 dosage with a random cohort effect.ResultWe examined 2,262 AA AD cases, including 1,561 females (69%) with mean (SD) AAO of 77.7 (8.1) years. The APOE‐adjusted COXPHF analyses identified twelve genome‐wide significant regions (P<5×10−8), the most significant in ABCA7 (P = 3.57×10−10), known to be associated with AD risk in AAs. In the LMM analysis, we observed strong novel associations with variants in CCDC141 on chr2q31.2 (Pmin = 2.93×10−9). In silico analyses of LD structure and functional potential suggest SESTD1, a gene involved in synaptic regulation, as driving the CCDC141 locus signal. Nine of 12 COXPHF loci were driven by African‐specific variants (MAF<0.0002 in gnomAD Non‐Finish Europeans). These significant loci identified in the AA COXPHF or LMM analyses were not significant (P>0.05) in equivalent analyses in NHW ADGC cohorts (9,220 AD cases/10,350 controls; Li et al. Alz Dement 2023), except for the ABCA7 locus (NHW P<0.0002).ConclusionIn a large ADGC African American dataset, we confirmed AAO associations in the APOE region and ABCA7 and observed evidence for potential novel AD AAO loci including SESTD1; many of which might be African‐ancestry specific.